Recommendations for pharmacological clinical trials in children with functional constipation: The Rome foundation pediatric subcommittee on clinical trials.

BACKGROUND: Evidence for the efficacy of commonly used drugs in the treatment of childhood functional constipation (FC) is scarce, studies are often of low quality and study designs are heterogeneous. Thus, recommendations for the design of clinical trials in childhood FC are needed. PURPOSE: Members of the Rome Foundation and a member of the Pediatric Committee of the European Medicines Agency formed a committee to create recommendations for the design of clinical trials in children with FC. KEY RECOMMENDATIONS: This committee recommends conducting randomized, double-blind, placebo-controlled, parallel-group clinical trials to assess the efficacy of new drugs for the treatment of childhood FC. Pediatric study participants should be included based on fulfilling the Rome IV criteria for FC. A treatment free run-in period for baseline assessment is recommended. The trial duration should be at least 8 weeks. Treatment success is defined as no longer meeting the Rome IV criteria for FC. Stool consistency should be reported based on the Bristol Stool Scale. Endpoints of drug efficacy need to be tailored to the developmental age of the patient population.

An ANMS-NASPGHAN consensus document on esophageal and antroduodenal manometry in children.

BACKGROUND: Upper gastrointestinal symptoms in children are common and motility disorders are considered in the differential diagnosis. High resolution esophageal manometry (HRM) has revolutionized the study of esophageal physiology, and the addition of impedance has provided new insights into esophageal function. Antroduodenal motility has provided insight into gastric and small bowel function. PURPOSE: This review highlights some of the recent advances in pediatric esophageal and antroduodenal motility testing including indications, preparation, performance, and interpretation of the tests. This update is the second part of a two part series on manometry studies in children (first part was on anorectal and colonic manometry [Neurogastroenterol Motil. 2016;29:e12944]), and has been endorsed by the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) and the American Neurogastroenterology and Motility Society (ANMS).

Spontaneous food allergy in Was-/- mice occurs independent of FcεRI-mediated mast cell activation.

BACKGROUND: Food allergies are a growing health problem, and the development of therapies that prevent disease onset is limited by the lack of adjuvant-free experimental animal models. We compared allergic sensitization in patients with food allergy or Wiskott-Aldrich syndrome (WAS) and defined whether spontaneous disease in Was-/- mice recapitulates the pathology of a conventional disease model and/or human food allergy. METHODS: Comparative ImmunoCAP ISAC microarray was performed in patients with food allergy or WAS. Spontaneous food allergy in Was-/- mice was compared to an adjuvant-based model in wild-type mice (WT-OVA/alum). Intestinal and systemic anaphylaxis was assessed, and the role of the high-affinity IgE Fc receptor (FcεRI) in allergic sensitization was evaluated using Was-/- Fcer1a-/- mice. RESULTS: Polysensitization to food was detected in both WAS and food-allergic patients which was recapitulated in the Was-/- model. Oral administration of ovalbumin (OVA) in Was-/- mice induced low titers of OVA-specific IgE compared to the WT-OVA/alum model. Irrespectively, 79% of Was-/- mice developed allergic diarrhea following oral OVA challenge. Systemic anaphylaxis occurred in Was-/- mice (95%) with a mortality rate >50%. Spontaneous sensitization and intestinal allergy occurred independent of FcεRI expression on mast cells (MCs) and basophils. CONCLUSIONS: Was-/- mice provide a model of food allergy with the advantage of mimicking polysensitization and low food-antigen IgE titers as observed in humans with clinical food allergy. This model will facilitate studies on aberrant immune responses during spontaneous disease development. Our results imply that therapeutic targeting of the IgE/FcεRI activation cascade will not affect sensitization to food.

Intra- and interrater reliability of the Chicago Classification of achalasia subtypes in pediatric high-resolution esophageal manometry (HRM) recordings.

BACKGROUND: Subtyping achalasia by high-resolution manometry (HRM) is clinically relevant as response to therapy and prognosis have shown to vary accordingly. The aim of this study was to assess inter- and intrarater reliability of diagnosing achalasia and achalasia subtyping in children using the Chicago Classification (CC) V3.0. METHODS: Six observers analyzed 40 pediatric HRM recordings (22 achalasia and 18 non-achalasia) twice by using dedicated analysis software (ManoView 3.0, Given Imaging, Los Angeles, CA, USA). Integrated relaxation pressure (IRP4s), distal contractile integral (DCI), intrabolus pressurization pattern (IBP), and distal latency (DL) were extracted and analyzed hierarchically. Cohen's κ (2 raters) and Fleiss' κ (>2 raters) and the intraclass correlation coefficient (ICC) were used for categorical and ordinal data, respectively. RESULTS: Based on the results of dedicated analysis software only, intra- and interrater reliability was excellent and moderate (κ=0.89 and κ=0.52, respectively) for differentiating achalasia from non-achalasia. For subtyping achalasia, reliability decreased to substantial and fair (κ=0.72 and κ=0.28, respectively). When observers were allowed to change the software-driven diagnosis according to their own interpretation of the manometric patterns, intra- and interrater reliability increased for diagnosing achalasia (κ=0.98 and κ=0.92, respectively) and for subtyping achalasia (κ=0.79 and κ=0.58, respectively). CONCLUSIONS: Intra- and interrater agreement for diagnosing achalasia when using HRM and the CC was very good to excellent when results of automated analysis software were interpreted by experienced observers. More variability was seen when relying solely on the software-driven diagnosis and for subtyping achalasia. Therefore, diagnosing and subtyping achalasia should be performed in pediatric motility centers with significant expertise.

Prospective evaluation of same day versus next day colon manometry results in children with medical refractory constipation.

BACKGROUND: We evaluated the change in colon manometry (CM) parameters and interpretation comparing results when the study is performed the same day after the motility catheter is placed under anesthesia or the following day. METHODS: CM catheter was placed with colonoscopy under anesthesia and recorded on day 1 and repeated on day 2. Study parameters including motility index during fasting, post-prandial and post-Bisacodyl challenge phase; gastrocolonic response; number, presence and propagation of high amplitude propagating contractions (HAPCs); and, study interpretation were compared between both the days. KEY RESULTS: Motility index (fasting, post-Bisacodyl phase, P<.05), HAPC number (10.1 vs 6.6, P=.01) and the proportion of patients having HAPCs (92% vs 70%, P=.002) was significantly higher on day 2 vs day 1. HAPC propagation improved on day 2 vs day 1 (fully propagated, 49% vs 37%; partially propagated, 43% vs 33%; absent 8% vs 30%). Study interpretation changed from day 1 to day 2. On day 1, 37% had a normal study and 63% had an abnormal study. On day 2, all patients with a normal study on day 1 remained normal, and patients with an abnormal study on day 1, 53% remained abnormal and 47% had a normal study. CONCLUSIONS & INFERENCES: CM parameters are affected the day the catheter is placed with colonoscopy under anesthesia. The number, presence, and propagation of HAPCs were significantly higher/improved on day 2 compared to day 1. Overall, CM interpretation changed from abnormal to normal from day 1 to day 2 in 47% of the patients.

Pediatric rumination subtypes: A study using high-resolution esophageal manometry with impedance.

BACKGROUND: The differential diagnosis of intractable reflux in children includes rumination syndrome, but confirming the diagnosis using antroduodenal manometry is invasive, is costly, and requires anesthesia. High-resolution esophageal manometry with impedance (HRM-MII) overcomes these limitations, and the goal of this study is to validate the use of HRM-MII as a diagnostic tool for rumination and to describe the subtypes of pediatric rumination. METHODS: We reviewed the HRM-MII tracings of 21 children presenting with symptoms of intractable reflux in whom rumination was being considered. Patients underwent a standard and post-prandial HRM-MII. Peak intraluminal esophageal pressures, baseline gastric and thoracic pressures, and the timing of the R wave relative to LES relaxations and bolus flow were recorded. Chi-square analyses were used for comparison of proportions and means were compared using t-tests or non-parametric equivalent. KEY RESULTS: Forty-one (55.5%) primary and 33 (44.5%) secondary rumination episodes were seen. Three types of primary rumination were identified: i) LES relaxation without retrograde flow preceding the R wave (51% of episodes); ii) LES relaxation after the R wave (20% of episodes); and iii) R waves with no LES relaxation (29% of episodes). Eleven patients had rumination episodes with a peak gastric pressure <30 mm Hg. A total of 44 (60%) rumination episodes occurred during the standard HRM-MII, and 30 (40%) occurred during or after the meal. CONCLUSIONS & INFERENCES: HRM-MII can accurately diagnose rumination in children. We identify three types of primary rumination which may provide insight into therapeutic response.

Simultaneous urodynamic and anorectal manometry studies in children: insights into the relationship between the lower gastrointestinal and lower urinary tracts.

BACKGROUND: Children with urinary incontinence (UI) have associated functional constipation (FC) and fecal incontinence (FI). The physiology between lower urinary tract (LUT) and anorectum in children has not been elucidated. AIMS: Observe the effect of rectal distention (RD) on LUT function, and bladder filling and voiding on anorectal function. METHODS: Children with voiding dysfunction referred to Boston Children's Hospital were prospectively enrolled in combined urodynamic (UDS) and anorectal manometry (ARM). Anorectal and urodynamic parameters were simultaneously measured. Patients underwent two micturition cycles, first with rectal balloon deflated and second with it inflated (RD). Lower urinary tract and anorectal parameters were compared between cycles. KEY RESULTS: Ten children (seven UI, four recurrent UTIs, nine FC ± FI) were enrolled. Postvoid residual (PVR) increased (p = 0.02) with RD. No differences were observed in percent of bladder filling to expected bladder capacity, sensation, and bladder compliance with and without RD. Bladder and abdominal pressures increased at voiding with RD (p < 0.05). Intra-anal pressures decreased at voiding (p < 0.05), at 25% (p = 0.03) and 50% (p = 0.06) of total volume of bladder filling. CONCLUSIONS & INFERENCES: The PVR volume increased with RD. Stool in the rectum does not alter filling cystometric capacity but decreases the bladder's ability to empty predisposing patients with fecal retention to UI and UTIs. Bladder and abdominal pressures increased during voiding, demonstrating a physiological correlate of voiding dysfunction. Intra-anal pressures decreased during bladder filling and voiding. This is the first time intra-anal relaxation during bladder filling and voiding has been described.

Primary Graft Dysfunction After Zero-Mismatch Kidney Transplantation Secondary to Early Biopsy-Proven Acute Cell-Mediated Rejection: Case Report.

We report a case of primary renal allograft dysfunction and early acute cell-mediated rejection after a 12/12 HLA antigen zero-mismatch (0MM) transplant. The recipient was a 40-year-old white man who was highly allosensitized, with a calculated panel reactive antibody score of 100%. In posteroperative day 1 the recipient remained anuric and underwent dialysis because of hyperkalemia. Graft biopsy showed early acute cellular rejection, Banff grade 2B. No evidence of antibody-mediated rejection was observed. To our knowledge, this case is the 1st to report early cell-mediated rejection after 12/12 HLA antigen 0MM kidney transplantation. This case suggests that highly sensitized candidates are at high immunologic risk even in the context of 0MM kidney transplantation.

Effect of anesthesia on gastroesophageal reflux in children: a study using BRAVO wireless pH study measurements.

BACKGROUND: Adult studies suggest conscious sedation increases gastroesophageal reflux (GER), but the role of anesthesia on GER in children is unclear. Our aim was to study the anesthesia effects on GER and pH study interpretation in children. METHODS: Children undergoing BRAVO wireless pH capsule placement under anesthesia and study duration >36 h were included. We evaluated the pH parameters (number of reflux episodes >5 min, duration of longest reflux episode, time pH <4 and fraction time pH <4) at 1, 2, 6-h and total study duration blocks using 2 cutoff values (5.3% and 6%) for the worst day, average of both days, and 1st day alone. We compared time blocks to evaluate the effect of anesthesia on GER and the proportions of studies changing interpretation after excluding the 1st hour and 1st 2-h blocks to evaluate anesthesia effect on study interpretation. KEY RESULTS: A total of 150 children were included. We found a significant increase on the pH parameters in the 1st hour compared to subsequent block times suggesting an effect of anesthesia on GER. We found no significant change in the proportion of studies interpreted as normal vs abnormal, however, excluding the initial 2 h of the study would change the study interpretation from abnormal to normal in up to 5% of patients. CONCLUSIONS & INFERENCES: We found an effect of anesthesia increasing the GER parameters mainly in the 1st hour and up to the first 6 h of the study that may result in a change in the study interpretation.

Inpatient burden of childhood functional GI disorders in the USA: an analysis of national trends in the USA from 1997 to 2009.

BACKGROUND: Functional gastrointestinal disorders (FGIDs) are among the most common outpatient diagnoses in pediatric primary care and gastroenterology. There is limited data on the inpatient burden of childhood FGIDs in the USA. The aim of this study was to evaluate the inpatient admission rate, length of stay (LoS), and associated costs related to FGIDs from 1997 to 2009. METHODS: We analyzed the Kids' Inpatient Sample Database (KID) for all subjects in which constipation (ICD-9 codes: 564.0-564.09), abdominal pain (ICD-9 codes: 789.0-789.09), irritable bowel syndrome (IBS) (ICD-9 code: 564.1), abdominal migraine (ICD-9 code: 346.80 and 346.81) dyspepsia (ICD-9 code: 536.8), or fecal incontinence (ICD-codes: 787.6-787.63) was the primary discharge diagnosis from 1997 to 2009. The KID is the largest publicly available all-payer inpatient database in the USA, containing data from 2 to 3 million pediatric hospital stays yearly. KEY RESULTS: From 1997 to 2009, the number of discharges with a FGID primary diagnosis increased slightly from 6,348,537 to 6,393,803. The total mean cost per discharge increased significantly from $6115 to $18,058 despite the LoS remaining relatively stable. Constipation and abdominal pain were the most common FGID discharge diagnoses. Abdominal pain and abdominal migraine discharges were most frequent in the 10-14 year age group. Constipation and fecal incontinence discharges were most frequent in the 5-9 year age group. IBS discharge was most common for the 15-17 year age group. CONCLUSIONS & INFERENCES: Hospitalizations and associated costs in childhood FGIDs have increased in number and cost in the USA from 1997 to 2009. Further studies to determine optimal methods to avoid unnecessary hospitalizations and potentially harmful diagnostic testing are indicated.

Inter- and intrarater reliability of the Chicago Classification in pediatric high-resolution esophageal manometry recordings.

BACKGROUND: The Chicago Classification (CC) facilitates interpretation of high-resolution manometry (HRM) recordings. Application of this adult based algorithm to the pediatric population is unknown. We therefore assessed intra and interrater reliability of software-based CC diagnosis in a pediatric cohort. METHODS: Thirty pediatric solid state HRM recordings (13M; mean age 12.1 ± 5.1 years) assessing 10 liquid swallows per patient were analyzed twice by 11 raters (six experts, five non-experts). Software-placed anatomical landmarks required manual adjustment or removal. Integrated relaxation pressure (IRP4s), distal contractile integral (DCI), contractile front velocity (CFV), distal latency (DL) and break size (BS), and an overall CC diagnosis were software-generated. In addition, raters provided their subjective CC diagnosis. Reliability was calculated with Cohen's and Fleiss' kappa (κ) and intraclass correlation coefficient (ICC). KEY RESULTS: Intra- and interrater reliability of software-generated CC diagnosis after manual adjustment of landmarks was substantial (mean κ = 0.69 and 0.77 respectively) and moderate-substantial for subjective CC diagnosis (mean κ = 0.70 and 0.58 respectively). Reliability of both software-generated and subjective diagnosis of normal motility was high (κ = 0.81 and κ = 0.79). Intra- and interrater reliability were excellent for IRP4s, DCI, and BS. Experts had higher interrater reliability than non-experts for DL (ICC = 0.65 vs ICC = 0.36 respectively) and the software-generated diagnosis diffuse esophageal spasm (DES, κ = 0.64 vs κ = 0.30). Among experts, the reliability for the subjective diagnosis of achalasia and esophageal gastric junction outflow obstruction was moderate-substantial (κ = 0.45-0.82). CONCLUSIONS & INFERENCES: Inter- and intrarater reliability of software-based CC diagnosis of pediatric HRM recordings was high overall. However, experience was a factor influencing the diagnosis of some motility disorders, particularly DES and achalasia.

Evaluation and treatment of functional constipation in infants and children: evidence-based recommendations from ESPGHAN and NASPGHAN.

BACKGROUND: Constipation is a pediatric problem commonly encountered by many health care workers in primary, secondary, and tertiary care. To assist medical care providers in the evaluation and management of children with functional constipation, the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition were charged with the task of developing a uniform document of evidence-based guidelines. METHODS: Nine clinical questions addressing diagnostic, therapeutic, and prognostic topics were formulated. A systematic literature search was performed from inception to October 2011 using Embase, MEDLINE, the Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials, and PsychInfo databases. The approach of the Grading of Recommendations Assessment, Development and Evaluation was applied to evaluate outcomes. For therapeutic questions, quality of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation system. Grading the quality of evidence for the other questions was performed according to the classification system of the Oxford Centre for Evidence-Based Medicine. During 3 consensus meetings, all recommendations were discussed and finalized. The group members voted on each recommendation, using the nominal voting technique. Expert opinion was used where no randomized controlled trials were available to support the recommendation. RESULTS: This evidence-based guideline provides recommendations for the evaluation and treatment of children with functional constipation to standardize and improve their quality of care. In addition, 2 algorithms were developed, one for the infants <6 months of age and the other for older infants and children. CONCLUSIONS: This document is intended to be used in daily practice and as a basis for further clinical research. Large well-designed clinical trials are necessary with regard to diagnostic evaluation and treatment.

Association of metabolic syndrome with kidney function and histology in living kidney donors.

The selection of living kidney donors is based on a formal evaluation of the state of health. However, this spectrum of health includes subtle metabolic derangements that can cluster as metabolic syndrome. We studied the association of metabolic syndrome with kidney function and histology in 410 donors from 2005 to 2012, of whom 178 donors were systematically followed after donation since 2009. Metabolic syndrome was defined as per the NCEP ATPIII criteria, but using a BMI > 25 kg/m(2) instead of waist circumference. Following donation, donors received counseling on lifestyle modification. Metabolic syndrome was present in 50 (12.2%) donors. Donors with metabolic syndrome were more likely to have chronic histological changes on implant biopsies than donors with no metabolic syndrome (29.0% vs. 9.3%, p < 0.001). This finding was associated with impaired kidney function recovery following donation. At last follow-up, reversal of metabolic syndrome was observed in 57.1% of donors with predonation metabolic syndrome, while only 10.8% of donors developed de novo metabolic syndrome (p < 0.001). In conclusion, metabolic syndrome in donors is associated with chronic histological changes, and nephrectomy in these donors was associated with subsequent protracted recovery of kidney function. Importantly, weight loss led to improvement of most abnormalities that define metabolic syndrome.

Elevated levels of leukotriene C4 synthase mRNA distinguish a subpopulation of eosinophilic oesophagitis patients.

BACKGROUND: Cysteinyl leukotrienes contribute to Th2-type inflammatory immune responses. Their levels in oesophageal tissue, however, do not distinguish patients with eosinophilic oesophagitis (EoE) from controls. OBJECTIVE: We asked whether mRNA levels of leukotriene C4 synthase (LTC4 S), a key regulator of leukotriene production, could serve as a marker for EoE. METHODS: Digital mRNA expression profiling (nCounter(®) Technology) was performed on proximal and distal oesophageal biopsies of 30 paediatric EoE patients and 40 non-EoE controls. Expression data were confirmed with RT-qPCR. LTC4 S mRNA levels were quantified in whole blood samples. Leukotriene E4 was measured in urine. RESULTS: LTC4 S mRNA levels were elevated in proximal (2.6-fold, P < 0.001) and distal (2.9-fold, P < 0.001) oesophageal biopsies from EoE patients. Importantly, increased LTC4 S mRNA transcripts identified a subpopulation of EoE patients (28%). This patient subgroup had higher serum IgE levels (669 U/mL vs. 106 U/mL, P = 0.01), higher mRNA transcript numbers of thymic stromal lymphopoietin (TSLP) (1.6-fold, P = 0.009) and CD4 (1.4-fold, P = 0.04) but lower IL-23 mRNA levels (0.5-fold, P = 0.04). In contrast, elevated levels of IL-23 mRNA were found in oesophageal biopsies of patients with reflux oesophagitis. LTC4 S mRNA transcripts in whole blood and urinary excretion of leukotriene E4 were similar in EoE patient subgroups and non-EoE patients. CONCLUSION & CLINICAL RELEVANCE: Elevated oesophageal expression of LTC4 S mRNA is found in a subgroup of EoE patients, concomitant with higher serum IgE levels and an oesophageal transcriptome indicative of a more-pronounced allergic phenotype. Together with TSLP and IL-23 mRNA levels, oesophageal LTC4 S mRNA may facilitate diagnosis of an EoE subpopulation for personalized therapy.

Relationship between postprandial metabolomics and colon motility in children with constipation.

BACKGROUND: The metabolic pathways associated with colonic motility are unknown. To identify potential metabolic targets for treatment of constipation, we examined the metabolic profile before and after a meal challenge in a cohort of children with constipation and determined its relationship with postprandial colon motility patterns. METHODS: In this prospective study, 187 metabolites were measured by liquid chromatography-mass spectrometry at multiple time points before and after a standardized meal in constipated children undergoing a colon manometry. Postprandial metabolite levels were compared with baseline and also correlated with multiple manometric measurements, including the number, frequency, and amplitude of pressure peaks as well as the motility index (MI). KEY RESULTS: A total of 20 subjects were included (mean age 13.1 ± 3.4 years). No significant metabolite changes were observed at 10 min after the meal, whereas 16 amino acid and 22 lipid metabolites had significant (P < 0.005) postprandial changes, including decreases in methylhistamine, histamine, and GABA, by 60 min. Correlations were observed between normal and abnormal postprandial motility patterns and changes in specific metabolites, including glycerol, carnosine, alanine, asparagine, cytosine, choline, phosphocholine, thyroxine, and triiodothyronine. Interestingly, subjects without the normal postprandial increase in area under the curve (AUC), had markedly increased levels of kynurenic acid and adenosyl-homocysteine. CONCLUSIONS & INFERENCES: This is the first study to examine postprandial metabolic changes in children and also to correlate changes in specific metabolites with colonic motility. The results suggest possible metabolic pathways associated with motility and identify potential targets for the treatment of constipation.

Factors associated with successful decrease and discontinuation of antegrade continence enemas (ACE) in children with defecation disorders: a study evaluating the effect of ACE on colon motility.

BACKGROUND: Antegrade continence enemas (ACE) have been used in the treatment of defecation disorders in children; little is known on their effect on colon motility and the utility of the colon manometry (CM) predicting long-term ACE outcomes. METHODS: Retrospective review of children with constipation undergoing CM before and after ACE to evaluate CM changes and their utility on predicting ACE outcome. KEY RESULTS: A total of 40 patients (mean age 8.8 SD 3 years and 53% female patients) were included; 39 of 40 responded to the ACE. Of these 39, 14 (36%) were dependent and 25 (64%) had decreased it (11 of those or 28% discontinued it). On repeat CM we found a significant increase in the fasting (P < 0.01) and postprandial (P = 0.03) motility index, number of bisacodyl-induced high amplitude propagating contractions (HAPCs) (P = 0.03), and total HAPCs (P = 0.02). Gastrocolonic response to a meal, propagation and normalization of HAPCs improved in 28%, 58%, and 33%, respectively, with CM normalizing in 33% of patients. The baseline CM did not predict ACE outcome. The presence of normal HAPCs on the repeat CM was associated with ACE decrease. Progression and normalization of HAPCs (P = 0.01 and 0.02, respectively) and CM normalization (P = 0.01) on repeat CM were individually associated with ACE decrease. No CM change was associated with ACE discontinuation. Multivariate analysis showed that older age and HAPC normalization on CM predict ACE decrease and older age is the only predictor for ACE discontinuation. CONCLUSIONS & INFERENCES: Colon motility improves after ACE and the changes on the repeat CM may assist in predicting ACE outcome.

Internal anal sphincter relaxation associated with bisacodyl-induced colonic high amplitude propagating contractions in children with constipation: a colo-anal reflex?

BACKGROUND: Describe the association of internal anal sphincter (IAS) relaxation with colonic high- amplitude peristaltic contractions (HAPCs). METHODS: Retrospective review of colon manometry tracings of children with constipation to determine the IAS relaxation characteristics associated with HAPC's (HAPC-IASR) events and compare them to the those seen during the performance of the anorectal manometry (ARMRAIR) events. KEY RESULTS: A total of 70 HAPC- IASRs were observed in 15 patients, 65 after bisacodyl, two during fasting and three after a meal. In 64% of events, the IAS relaxation started when the HAPC reached left colon and in 36% as proximal as the hepatic flexure. High- amplitude peristaltic contraction propagation seems to be important in HAPC-IASR characteristics; those propagating distal to sigmoid colon demonstrated larger and longer IAS relaxation as well as lower residual pressure, but equivalent resting pressure compared with HAPC's ending proximal to sigmoid colon. Although IAS resting pressure was comparable for ARM-RAIRs and HAPC-IASRs, the duration and magnitude of anal relaxation was higher, and the anal residual pressure was lower in HAPC-IASRs. CONCLUSIONS & INFERENCES: We demonstrated that IAS relaxation in constipated children is associated with HAPCs migrating in the proximal and distal colon; in most cases, starting when peristalsis is migrating through left colon and in an important proportion while migrating proximally. We also demonstrated that HAPC-IASRs are different from ARM-RAIRs suggesting a neurally mediated reflex. Finally, the IAS relaxation characteristics are highly dependent on the degree of propagation of HAPCs, which could have important implications in the understanding of defecation disorders.

The presence of pepsin in the lung and its relationship to pathologic gastro-esophageal reflux.

BACKGROUND: Pepsin has been proposed as a biomarker of reflux-related lung disease. The goal of this study was to determine (i) if there is a higher reflux burden as measured by pH-MII in patients that are pepsin positive in the lung, and (ii) the sensitivity of pepsin in predicting pathologic reflux by pH, MII, and EGD. METHODS: We recruited children between the ages of 1-21 with chronic cough or asthma undergoing bronchoscopy, esophagogastroduodenoscopy (EGD), and multichannel intraluminal impedance (pH-MII) probe placement. The reflux profiles were compared between those patients who were pepsin positive and negative; proportions were compared using Chi-squared analyses and means were compared using t-testing. KEY RESULTS: Only the mean number of non-acid reflux events was associated with pepsin positivity (0.04). The sensitivity and specificity of pepsin in predicting pathologic reflux by pH-MII or EGD was 57% and 65%, respectively. The positive predictive value of pepsin in predicting pathologic reflux by pH, MII or EGD was 50% (11/22), and the negative predictive value was 71% (20/28). There was a significantly higher mean LLMI in patients who were pepsin positive compared with pepsin negative patients (81 ± 54 vs 47 ± 26, P = 0.001). CONCLUSIONS & INFERENCES: Lung pepsin cannot predict pathologic reflux in the esophagus, but its correlation with lung inflammation suggests that pepsin may be an important biomarker for reflux-related lung disease.

Diagnosis of supra-esophageal gastric reflux: correlation of oropharyngeal pH with esophageal impedance monitoring for gastro-esophageal reflux.

BACKGROUND: Oropharyngeal (OP) pH monitoring has been developed as a new way to diagnose supra-esophageal gastric reflux (SEGR), but has not been well validated. Our aim was to determine the correlation between OP pH and gastro-esophageal reflux (GER) events detected by multichannel intraluminal impedance-pH (MII-pH). METHODS: Fifteen patients (11 males, median age 10.8 years) with suspected GER were prospectively evaluated with ambulatory 24-h OP pH monitoring (positioned at the level of the uvula) and concomitant esophageal MII-pH monitoring. Potential OP events were identified by the conventional pH threshold of <4 and by the following alternative criteria: (i) relative pH drop >10% from 15-min baseline and (ii) absolute pH drop below thresholds of <5.5, 5.0, and 4.5. The 2-min window preceding each OP event was analyzed for correlation with an episode of GER detected by MII-pH. KEY RESULTS: A total of 926 GER events were detected by MII-pH. Application of alternative pH criteria increased the identification of potential OP pH events; however, a higher proportion of OP events had no temporal correlation with GER (45-81%), compared with the conventional definition of pH < 4 (40%). A total of 306 full-column acid reflux episodes were detected by MII-pH, of which 10 (3.3%) were also identified by OP pH monitoring. CONCLUSIONS & INFERENCES: Use of extended pH criteria increased the detection of potential SEGR events, but the majority of decreases in OP pH were not temporally correlated with GER. Oropharyngeal pH monitoring without concurrent esophageal measurements may overestimate the presence of SEGR in children.

Coexistence of constipation and incontinence in children and adults.

The coexistence of constipation and fecal incontinence has long been recognised in paediatric and geriatric populations, but is grossly underappreciated in the rest of the adult population. In children, functional fecal incontinence is usually associated with constipation, stool retention and incomplete evacuation, and is frequently allied to urinary incontinence. Pathophysiology of the incontinence is incompletely understood, although both in children and adults, it is thought to be secondary to overflow, while in adults it may also be related to pelvic floor dysfunction and denervation. Incontinence has an important impact on quality of life and daily functioning, and in children may be associated with behaviour problems. The treatment of underlying constipation usually results in improvement in incontinence. This review broadly addresses the epidemiology and pathophysiology of coexistent constipation and incontinence in both children and adults, and also reviews clinical presentation and treatment response in pediatrics.